It is known that molecules containing the chromo/fluorophore phthalocyanine macrocycle produce reactive species of oxygen, such as radicals or singlet oxygen, by interaction with visible light.
For these properties phthalocyanine compounds have proposed in photodynamic therapy (hereinafter indicated with the initials “PDT”) both for therapeutic treatment and for diagnostic purposes prior treatment.
Examples of these compounds are described by Ogura et al. Journal of Porphyrins and Phthalocyanines 2006, 10, 1116-1124.
Photosensitizing agents useful in PDT are Zinc phthalocyanine compounds and their conjugates described in the patent EP 906 758, by the Applicant.
Moreover, EP 1 444 236 and in EP 1 883 640 (both by the Applicant) respectively describe a process for the separation of regioisomers mixtures and a process for the preparation of chlorides of phthalocyanine compounds.
The compounds described and obtained according to the processes indicated in the above documents have proven to be effective photosensitising agents in PDT treatment, both for tumours and for microbial infections; in particular the product [1,8(11),15(18),22(25)-tetrakis-(3-N,N,N-trimethylammonium phenoxy)] zinc phthalocyaninate tetraiodide, corresponding to example 53 of EP 906 758, has proved to be particularly active. It is known that tetra-substituted phthalocyanine derivatives, such as the compound [1,8(11),15(18),22(25)-tetrakis-(3-N,N,N-trimethylammonium phenoxy)] zinc phthalocyaninate tetraiodide, corresponding to example 53 of EP 906 758, are obtained as a mixture of four positional isomers (see FIG. 1), identified according to the symmetry classes (D2h, C4h, Cs, C2v), and hereinafter respectively named with the letters of the alphabet (A, B, C, D). The aforesaid isomers are formed during the synthesis of the phthalocyanine macrocycle in relative percentages which differ from the theoretical (defined by statistics and respectively equal to 12.5%, 12.5%, 50% and 25%) as a function of the synthesis method used, the nature of the phthalonitrile substituents employed for preparation and, finally, of the central metal inserted, but which are constant, given the same compound and method (Phthalocyanines: Properties and Applications, Volume 4, Chapter 1 C. C. Leznoff and A. B. P. Lever (York University, Canada). VCH: New York, 1996).
As a result, a particular compound, prepared through a specific synthesis method, such as example 53 of EP 906 758, will have a typical and reproducible isomers distribution.
Also using the synthesis process described in the patent EP 1 883 640, through which the compound [1,8(11),15(18),22(25)-tetrakis-(3-N,N,N-trimethylammonium phenoxy)] zinc phthalocyaninate is obtained as tetrachloride (example 4), the new salt is in any case present as a mixture of four isomers, according to the isomers distribution expected and already obtained with the process indicated in EP 906 758.
The exact isomers distribution of a particular tetra-substituted phthalocyanine derivative can be known and controlled using the separation process described in the patent EP 1 444 236.
During characterization studies of [1,8(11),15(18),22(25)-tetrakis-(3-N,N,N-trimethylammonium phenoxy)] zinc phthalocyaninate (tetraiodide or tetrachloride), the Applicant has discovered that the compound identified above, obtained by following known synthesis processes, contains related substances in a percentages greater than 0.1%, whose reduction/elimination is difficult to achieve. Even using the synthesis process described in the European Patent EP 1 883 640, and therefore preparing said compound as chloride (example 4), although obtaining an improvement in terms of solubility and product purity, it is not possible to reduce said impurities in the final product below 0.1% by weight (threshold above which structural identification and toxicological qualification is required).
Moreover the related substances described above have considerable structural similarities compared to the active substance, are able to interact with the light radiation used in PDT and, unlike all other impurities, cannot be eliminated from batches of the ammonium derivative [1,8(11),15(18),22(25)-tetrakis-(3-N,N,N-trimethylammonium phenoxy)] zinc phthalocyaninate (tetraiodide or tetrachloride). Therefore, there is still the need of improving the purity of the compound [1,8(11),15(18),22(25)4tetrakis-(3-N,N,N-trimethylammonium phenoxy)] zinc phthalocyaninate tetrachloride, in view of its use as a drug substance.